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Monster cancer chromosome is made from shattered DNA

By Michael Slezak

WHEN chromosomes shatter, they sometimes reform into giant circular monsters. These beasts gobble up cancer genes, incorporate them into their DNA, and seed aggressive tumours. They are an example of the giant leaps of evolution that cancer can take, but they could also lead to drugs that stop the process.

In the 1950s, researchers saw that some cancer cells contained chromosomes that were unusually large and sometimes circular. Called neochromosomes, they’ve since been found in about 3 per cent of all cancers and in almost a quarter of fat and bone cancers, but nobody has known how they form or what they do.

Now for the first time, David Thomas from the Garvan Institute in Sydney, Australia, and his colleagues have sequenced these giant chromosomes and reconstructed their evolutionary history. They looked at three different sets of lab-grown liposarcoma cells – a cancer of fat and connective tissues. In some of the neochromosomes, they found DNA from every other chromosome. What’s more, genes known to be important for cancer were repeated between 60 and 100 times in the monster, massively amplifying their effect. Some of the neochromosomes had three times as much DNA in them as the largest normal chromosomes.

Modelling showed that the main changes to the structure of these chromosomes don’t occur incrementally. Rather, it suggests a bizarre developmental process. First a chromosome is catastrophically shattered when it loses the caps on its ends, known as telomeres, that hold it together. Natural DNA-repair mechanisms then kick in and put the pieces back together, but in a complete hotchpotch, which usually means the cell will die. This process, discovered in 2010, is called chromothripsis. Occasionally, though, these chromosomal oddities survive and, without telomeres, their ends join together in a ring (see diagram).

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Then you have the makings of the monster, says Thomas. Each subsequent time a cell divides, these circular chromosomes are torn apart unevenly. One chunk gets a bigger section than the other, meaning it loses some genes and picks up repeats of others. Over thousands of divisions, it grows. It also picks up bits of DNA from any other chromosomes that also happen to have shattered.

But the team found the monster is much more likely to pick up repeats of genes known to be important to cancer. “There’s selection going on,” says Thomas. To test whether those cancer genes help the cell survive, they tried blocking them. When the genes were blocked, the cell died (Cancer Cell, doi.org/w3h).

The monsters don’t stay circular for ever. At a certain point, the circle stops growing and becomes linear. It does that by grabbing telomeres from other chromosomes, which makes it straight and stable again.

The evolutionary path of the neochromosomes is amazing, says Charles Swanton from Cancer Research UK in London. He says it’s like the picture described by Jeff Goldblum’s character in Jurassic Park. “Life finds a way,” Swanton says, quoting the movie.

Andrew Wagner at the Dana-Farber Cancer Institute in Boston likens the approach of sifting through shattered chromosomes to archaeology. “It provides great insight into how cancer cells can select for elements of DNA that help their proliferation and survival,” he says.

Sifting through shattered chromosomes is like archaeology, and it shows how cancer survives

It’s not the whole story of the cancer, because not all cancers have these chromosomes in them, and it’s not the only step these cancers need, says Thomas. But it could be an important process in understanding cancer development, he says, much as the discovery of the BRCA breast cancer mutations was.

Because the genes that are massively amplified in the neochromosomes are essential for the cell’s survival, drugs that turn those off are an obvious target for research. Thomas says there are already human trials of drugs that seem to do that.

This article appeared in print under the headline “Evolution of a genetic monster”